tbuckley/cabot-search huggingface dataset:
Abstract 12422: Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Are Mutually Independent Predictors of Major Cardiovascular Events in Patients With Established Cardiovascular Disease
Authors: Lukas Sprenger, Maximilian Maechler, Alexander Vonbank, Barbara Larcher, Arthur Mader, Andreas Leiherer, Axel Muendlein, Heinz Drexel, Christoph H Saely
Journal: Circulation (2022)

Introduction: Non-Alcoholic Fatty Liver Disease (NAFLD) is associated with insulin resistance, type 2 diabetes (T2DM) and cardiovascular disease. However, data on NAFLD in patients with established cardiovascular disease (CVD) are scarce. Hypothesis: We hypothesize that NAFLD and T2DM are independent predictors of the incidence of major cardiovascular events (MACE). Methods: In a large series of 1517 patients with established CVD (1199 patients with angiographically proven coronary artery disease and 318 patients with sonographically proven peripheral artery disease), using the validated fatty liver index for the diagnosis of NAFLD. Results: At baseline, the prevalence of NAFLD was significantly higher in patients with T2DM than in non-diabetic subjects (61.3% vs. 39.8%; p&lt;0.001) respectively. Prospectively, we recorded 498 MACE over a mean follow-up period of 10.0±4.5 years. The risk of MACE was higher in NAFLD patients than in those who did not have NAFLD (49.5 vs. 43.5%; p=0.020) and in patients with T2DM than in non-diabetic subjects (41.4 vs. 28.1%; p&lt;0.001). Cox regression models adjusting for conventional cardiovascular risk factors proved NAFLD and T2DM to be mutually independent predictors of MACE, with adjusted hazard ratios of 1.34 [1.06-1.69] p=0.013 and 1.59 [1.32-1.92]; p&lt;0.001, respectively. Conclusions: We conclude that NAFLD and T2DM are mutually independent predictors of MACE in patients with established CVD.
Abstract 11434: Soluble Programed Cell Death Ligand-1 is Associated With Future Heart Failure Hospitalization in Patients With Atherosclerotic Cardiovascular Disease
Authors: Atsushi Nozuhara, Shuhei Miyazaki, Koichiro Fujisue, Kenshi Yamanaga, Eiichiro Yamamoto, Koichi Egashira, Takashi Komorita, Daisuke Sueta, Hiroki Usuku, Satoshi Araki, Seiji Takashio, Kenichi Matsushita, Kenichi Tsujita
Journal: Circulation (2022)

&lt;Background&gt; Heart failure following atherosclerotic cardiovascular disease (ASCVD) is a significant problem worldwide. Chronic inflammation is a crucial pathogenesis both in heart failure and ASCVD. Programmed cell death-1(PD-1) and its ligand (PD-L1) regulate immune response through T cell proliferation and secretion of cytokines as immune checkpoint protein. However, the prognostic significance of immune checkpoint protein on ASCVD and heart failure is unknown. We investigated the association between the serum levels of PD-L1 (sPD-L1) and heart failure-related events in patients with ASCVD. &lt;Methods&gt; We prospectively measured sPD-L1 using a commercially available enzyme-linked immunosorbent assay kit in patients with ASCVD admitted to Kumamoto University Hospital. The occurrence of cardiovascular events was observed between December 2017 and January 2020. The primary outcome was heart failure hospitalization. We excluded patients complicated with cancer, hemodialysis, active collagen diseases, and inflammatory diseases. &lt;Results&gt; We screened 792 patients with ASCVD. 200 patients met exclusion criteria. Finally, 592 patients with ASCVD were enrolled. Median follow-up period was 490 days. A total of 37 events were recorded during study period. Kaplan-Meier curve revealed that the higher sPD-L1 group (sPD-L1≧136pg/dL, median) showed significantly higher rate of heart failure hospitalization than the lower sPD-L1 group (9.1% vs. 3.4%, log-rank test: P =0.006). Univariate Cox proportional hazards analysis identified estimated glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP), and higher sPD-L1 as significant factors associated with heart failure hospitalization. Multivariable Cox proportional hazards analysis by significant factors from univariate analysis identified that higher sPD-L1 [hazard ratio (HR): 1.003, 95% confidence interval (CI): 1.000-1.005, P =0.042) and BNP (HR: 1.001, 95% CI: 1.000-1.001, P =0.007)] were significantly and independently associated with heart failure hospitalization. &lt;Conclusion&gt; The higher levels of sPD-L1 were significantly associated with future heart failure hospitalization in patients with ASCVD.
Abstract 12043: The Genetic Variant P.(Lys3344Glu) in <i>APOB</i> Causes Familial Hypercholesterolemia
Authors: Ana Cenarro, Unai Galicia-Garcia, Victoria Marco-Benedi, ANA M BEA, Cesar Martin, Fernando Civeira
Journal: Circulation (2022)

Introduction: Genetic variation in the APOB gene is frequent but the pathogenicity of most of the variations is unknown. Only the variant in APOB p.(Arg3527Gln), known as familial defective apoB100, unequivocally produces familial hypercholesterolemia (FH). Hypothesis: A new variant in APOB responsible for HF in three unrelated Spanish families is presented. Its pathogenesis has been demonstrated by family segregation and apoB-LDL receptor binding analysis. Methods: The three probands correspond to two women and one man referred for study of their hypercholesterolemia at the Lipid Unit of the Miguel Servet Hospital in Zaragoza, Spain. Secondary causes were ruled out and family history showed a dominant segregation of hypercholesterolemia in their families. Their clinical characteristics are described in the table. Results: Sequencing analysis of the LDLR, APOB, PCSK9 , and APOE genes showed the c.10030A&gt;G; p.(Lys3344Glu) variant. No other pathogenic mutations were found.The family study included 14 first-degree relatives, with 8 of them being carriers of the APOB variant with a mean age of 42.5 years. The mean (range) of LDLc was 309 mg/dL (254-419) in carriers and 147 (98-179) in unaffected relatives. The apoB-LDL receptor binding study of the serum of the 3 probands (EC50) showed a reduction equivalent to that obtained with apoB p.(Arg3527Gln), and approximately 50% lower than that obtained in control serum. Conclusions: The p.(Lys3344Glu) variant in APOB is causal for FH and its mechanism is a defect in the affinity of the defective protein for the LDL receptor.
Abstract 13268: Associations Between Plant-Based Dietary Patterns and Risks of Type 2 Diabetes, Cardiovascular Disease, Cancer, and Mortality - A Systematic Review and Meta-Analysis
Authors: Yeli Wang, Yang Hu, Lu Zhu, Qi Sun
Journal: Circulation (2022)

Introduction: Plant-based dietary patterns that emphasize foods derived from plant sources and limit consumption of animal products have the potential to prevent and manage major chronic diseases. We aim to assess the existing prospective observational evidence on associations between adherence to plant-based dietary patterns and risk of developing type 2 diabetes (T2D), cardiovascular disease (CVD), cancer, and mortality. Methods: A s ystematic review and meta-analysis on prospective observational studies of plant-based dietary patterns and outcomes of T2D, CVD, cancer, and mortality was conducted. We searched PubMed and MEDLINE, Embase, and Web of Science, and screened references. Results: A total of 67 studies were identified, including 3,826,137 participants with 40,885 cases of incident T2D, 145,187 CVD cases, 25,510 cancer cases, and 75,412 deaths. An inverse association was observed between higher adherence to a plant-based dietary pattern and lower risks of T2D (RR, 0.80 [95% CI: 0.74-0.85]), CVD (0.89 [0.84-0.94]), and all-cause mortality (0.85 [0.76-0.95]) with a modest heterogeneity across studies ( I 2 ranged: 62.8%-96.2%), whereas a non-significant inverse association was observed for cancer risk (0.94 [0.87-1.01]; I 2 =49.2%). The inverse association with cancer was strengthened and became significant when healthy plant-based foods, such as vegetables, fruits, whole grains, and legumes, were included in the definition of plant-based dietary patterns (0.90 [95% CI: 0.81-0.99; I 2 =41.0%]). Among seven studies with measurements of changes in dietary patterns, increased adherence to a plant-based dietary pattern was significantly associated with lower risks of T2D (0.82 [0.71-0.95]; I 2 =72.2%) and mortality (0.95 [0.91-1.00]; I 2 =0%). Conclusions: Higher adherence to a plant-based dietary patterns, especially from healthy resources, may be beneficial for the primary prevention of T2D, CVD, cancer, and mortality.
Abstract 12294: Gut Microbial Features Associated With Sedentary Time But Not Physical Activity: Results From the Hispanic Community Health Study / Study of Latinos (HCHS/SOL)
Authors: Jee-Young Moon, Juan Lin, Daniela Sotres-Alvarez, Neil Schneiderman, Martha L Daviglus, Bharat Thyagarajan, Carlos Rodriguez, Qibin Qi, Robert Burk, Vasan S Ramachandran, Yasmin Mossavar-Rahmani, Robert Kaplan
Journal: Circulation (2022)

Introduction: Modest experimental and human evidence implicate a role for physical activity or sedentary lifestyle in the perturbation of the gut microbiome, yet large human studies are lacking. Methods: This study included 1846 US Hispanic/Latino adults without diabetes aged 23-82 years (mean age 48 years, 49% women) with gut microbiome data by shotgun sequencing of stools and accelerometer-measured moderate-to-vigorous physical activity (MVPA) and sedentary time from the HCHS/SOL population based cohort (2014-2017). We examined associations of MVPA and sedentary time with gut microbial features - Bray-Curtis dissimilarity by PERMANOVA, and alpha diversity and centered log ratio transformed relative abundance of species and KEGG pathway modules by a linear regression accounting for the complex survey design. Results: Prolonged sedentary time was associated with higher Shannon index (0.03 per 1 hr of sedentary time, SE=0.02, P=0.077) and Bray-Curtis dissimilarity (R 2 =0.32%, P&lt;0.001), adjusting for age and sex, but MVPA showed no association. Among 197 species with at least 0.01% average relative abundance, sedentary time was positively associated with 30 species including 8 Bacteroides species, Alistipes putredinis and finegoldii , and inversely with 19 species including 7 Prevotella species, Roseburia faecis , and Bifidobacterium adolescentis (FDR &lt;.1, Figure), whereas no species was associated with MVPA. A KEGG pathway module analysis suggested elevated methane metabolism, bacterial secretion, and carbon fixation with higher sedentary time (P&lt;.05) but none after FDR correction (all FDR&gt;.1). Positive associations were observed between MVPA with D-glucuronate degradation and semi-phosphorylative Entner-Doudoroff pathway (gluconate → glycerate-3P, found in halophilic euryachaea and Clostridium species) (P&lt;.05 but FDR&gt;.1). Conclusions: We observed a perturbed overall gut microbiome and relative abundance of species with sedentary time.
Abstract 11913: <i>In vivo</i> Optical Coherence Tomography Angiography of the Coronary Microcirculation
Authors: Yirong Zhou, Junyoung Kim, Guillermo J Tearney, Aaron D Aguirre
Journal: Circulation (2022)

Introduction: Imaging the coronary microcirculation in the beating heart is challenging due to motion artifact from cardiac contraction and respiration, which limits the application of high-resolution microscopy techniques. In the brain and other tissues with less motion artifact, optical coherence tomography angiography (OCTA) has been successfully used in rodents to create label-free maps of blood flow down to the capillary level. We hypothesized that advanced cardiac and respiratory gating together with high-speed optical coherence tomography can be used to implement OCTA of the capillary microcirculation in vivo in the mouse heart. Methods: C57BL/6 mice (n=30) were imaged through a sternotomy while anesthetized and ventilated. OCTA was performed using a custom tissue stabilizer and a Thorlabs TEL 321 Spectral Domain OCT system, which was synchronized to physiologic signals using custom hardware and software and cardiac pacing protocols. The system had an optical center wavelength of 1300 nm and produced axial (depth) and lateral resolutions of 4.2 μm and 13 μm, respectively. Angiograms were created from the difference between two consecutive images acquired during diastole, and a volumetric three-dimensional scan was acquired over multiple cardiac cycles. Images were analyzed in MATLAB and ImageJ to produce projection angiograms of the coronary microcirculation. Results: OCTA with cardiac and respiratory gating can produce high-resolution angiograms of the coronary microcirculation without exogenous contrast agents. OCTA has improved imaging depth and field of view compared to conventional confocal microscopy, and can produce widefield coronary angiograms (Fig. 1A) while maintaining the ability to visualize individual capillaries (Fig. 1B). Conclusion: In vivo OCTA can image the coronary microcirculation in the heart and will provide a powerful new tool for investigating coronary microvascular dysfunction in mouse models of heart disease.
Abstract 12718: ST Segment Elevation Myocardial Infarction Case With a Novel Therapy
Authors: Judit Karacsonyi, Miho Fukui, Spyridon Kostantinis, Bahadir Simsek, Emmanouil S Brilakis
Journal: Circulation (2022)

History: A 78-year-old man presented with anterior ST-segment elevation. Coronary angiography demonstrated an occluded left anterior descending coronary artery (LAD Figure 1A) with stenosis of the left circumflex (Cx) coronary artery. Procedure: The LAD was crossed with a workhorse wire (Figure 1B). Predilation restored the flow in the LAD and two diagonal branches (Figure 1C). After assessing the lesion with intravascular imaging (Figure 1D), two drug-eluting stents (DES) were deployed with provisional technique (Figure 1E). The diagonal was rewired and dilated with a 2.0 mm balloon (Figure 1F). A 3.5x20 mm DES was deployed covering the proximal LAD lesion (Figure 1G). The Cx ostium appeared pinched, but the diastolic pressure ratio was 0.95, hence no PCI was performed. Given the large MI size, we administered super saturated oxygen (SSO2). A 5F FR5 catheter was inserted into the LM ostium and SSO2 was administered for 1 hour. An excellent final angiographic result was achieved with TIMI 3 flow and well-expanded stents (Figure 1H). Peak creatinine kinase was 5840 U/l. Magnetic resonance imaging on the next day showed small thrombi, prominent microvascular obstruction in the mid LAD territory, and transmural infarction (Figure 1I). Left ventricular ejection fraction of 39% with normal left ventricular volume. The patient was discharged 3 days later on dual antiplatelet therapy and warfarin and referred to cardiac rehabilitation. Conclusion: “Time is muscle”, hence immediate revascularization is essential. Large anterior STEMIs may benefit from SSO2.
Abstract 11953: Sudden Death Associated With Therapeutic Levels of Methadone: Significance of Drug Interactions
Authors: Faye L Norby, Kyndaron Reinier, Sean Hennessy, Audrey Uy-Evanado, Harpriya Chugh, Arayik S Sargsyan, Angelo Salvucci, Jonathan Jui, Sean Hurst, Christopher Young, Sumeet S Chugh
Journal: Circulation (2022)

Introduction: Methadone for treatment of addiction or chronic pain can be complicated by QT interval prolongation and increased risk of sudden cardiac death (SCD). The concurrent use of additional QT-prolonging medications, such as selective serotonin reuptake inhibitors (SSRIs), may contribute to additional increased risk. We conducted a community-based study to assess the potential role of drug combinations in SCD. Methods: We ascertained residents of Multnomah Co., OR (2002-18) and Ventura Co., CA (2015-21) who suffered SCD and had toxicology reports available. We excluded those under age 18 and those with evidence of recreational drug use or drug overdose. Methadone levels and medications were captured on toxicology reports from the medical examiner. We used logistic regression to compare characteristics and the presence of select medications in those with and without therapeutic levels of methadone at the time of SCD. Results: Of the 789 subjects who met our criteria, the mean (25th-75th percentile) age was 49 (39-59) years, 34% were females, and 85 (11%) had therapeutic levels of methadone. Subjects on methadone were younger, more likely to be female, and had a higher prevalence of SSRIs and benzodiazepines compared to those without methadone (Table). Subjects with methadone had a 3.37 higher odds of SSRI use compared to those without methadone (95% CI: 1.87-6.09). When stratified by mechanistic category, those with methadone had higher odds of QT-prolonging SSRIs [OR (95% CI) = 2.87 (1.35-6.13)] and higher odds of other SSRIs [OR (95% CI) = 3.20 (1.40-7.32)] compared to those without methadone. Combinations of methadone with other selected drug classes did not reach statistical significance. Conclusion: These postmortem findings suggest that the combination of methadone with SSRIs may be associated with additional risk of SCD and warrant further investigation. Drug interactions are a potentially avoidable risk factor for SCD in patients receiving methadone.
Abstract 12313: Uncovering Functional and Structural Remodeling Progression of Persistent Atrial Fibrillation Over Time in a Rapid Atrial Pacing Canine Model - New Mechanistic Insights in Persistent Atrial Fibrillation
Authors: Markus Rottmann, Shin Yoo, Anna Pfenniger, Bradley P Knight, Rod Passman, Daniel C Lee, Rishi Arora
Journal: Circulation (2022)

Introduction: The specific underlying persistent AF mechanisms are complex, and their development and remodeling processes over time are still not well understood. Hypothesis: We hypothesized that continuous rapid atrial pacing (RAP) in dogs induces persistent AF by affecting electrogram measures, fibrosis and oxidative stress (OS). Methods: AF was induced in 15 dogs (25-35 kg, 1 year) by RAP (3-14 weeks RAP, 600 beats/min), and 7 control dogs were used. We performed high-resolution epicardial mapping in 15 dogs and 8 controls using a high-density epicardial mapping plaque (6 regions, 130 electrodes, electrode distance 2.5mm) ( Figure A ). We analyzed the electrogram measures cycle length (CL) and dominant frequency (DF) in the 6 atrial regions in the left (LA) and right atrium (RA). MRI native T1 mapping was performed using a 1.5T clinical scanner (Siemens Aera) in 7 persistent AF dogs and in 8 dogs at baseline in the posterior left atrium (PLA). We quantified in 6 atrial regions in both atria the oxidative stress (OS) levels as the ratio of oxidatively damaged nuclei against the total number in 8-OHdG staining in (N=36 samples in 6 animals) and the degree of dense fibro-fatty tissue in Masson’s trichrome stained tissue (N=24 in 4 animals) using Qupath in all 6 regions in both atria. Results: Rapid atrial pacing (RAP) weeks correlated with CL (R=0.6, P 0.05) in the PLA ( Figure B ). Native T1 signal intensity increased with RAP days (R=0.6, P 0.05) in the PLA (less than 142 pacing days) ( Figure C ). Highest degree of dense focal fibrosis/ fat was in the left atrial free wall (LAFW) (49+/-14%) and in the PLA (47+/-19%) ( Figure F ). OS levels, highest in the LAFW, lowest in the appendages increased with the degree fibrosis (R=0.6, P&lt;0.05) and with decreasing cycle length (R=0.5, P&lt;0.05) in all atrial regions ( Figure D,E,G,H,I ). Conclusions: Continuing persistent AF is associated with smaller CL, increasing fibrosis, and oxidative injury rapid atrial pacing time.
Abstract 12013: Nuclear Localization of PDGFRa Tyrosine Kinase Represents a Novel Mechanism Controlling the Fibrotic Response of Mesenchymal Stromal Cells to Myocardial Ischemia
Authors: Maria Paola Santini, Kiyotake Ishikawa, Evren Azeloglu
Journal: Circulation (2022)

Background: We discovered a time dependent dual role role for mesenchymal stromal cells expressing the platelet-derived growth factor alpha (PDGFRα + MSCs), which play essential functions in tissue revascularization and in fibro-adipogenic repair. Hypothesis: Based on our preliminary data, we hypothesized that specific and distinct stromal cells exist in the vertebrate heart, which retain regenerative capacities relevant to the extension of disease. Methods: All animal studies were performed in compliance with the regulations of the NIH and the local institutional animal care. Myocardial ischemia/reperfusion (MI/R) was induced in mice (n=10, FVB female mice) and pigs (n=10 female Yorkshire pigs) with standard procedures. Control animals were not operated (n=3 mice and n=4 pigs). Bulk RNA sequencing (n=4) was performed using a HiSeq2500 (Illumina). Results: Here, we showed that cardiac PDGFRα + MSCs have the potential to revascularize cardiac tissue and likely control cardiac electromechanical properties only earlier after MI/R. During the subacute phase, we discovered nuclear shuttling of the receptor from the plasma membrane before lineage specification into fibrotic cells (nuclear PDGFRα in non-ischemic 3±1 versus ischemic 7.7±2.5 hearts; p&lt;0.05). Interestingly, a similar response was observed in the heart of large animals (i.e., pigs), suggesting a cross-species mechanism controlling PDGFRα + MSCs commitment via intracellular shuffling of the tyrosine kinase receptor. A roadblock to the clinical translation of these discoveries is that there is no mechanism to manipulate PDGFRα + MSCs dual function. To cover this gap, we compared the transcriptomics of murine cardiac and skeletal muscle PDGFRα + MSCs using bulk RNA sequencing in physiological conditions. We discovered that key pathways, likely a signature of non-regenerating stromal cells, are differentially regulated in cardiac PDGFRα + MSCs, including Notch mediators of mesenchymal lineages and IGF-1 signaling. Conclusions: These data suggest that by modulating PDGFRα intracellular shuttling or altering the expression of specific genes, it may be possible to therapeutically direct PDGFRα + MSCs duality to reduce fibrosis, while harnessing their beneficial properties.
Abstract 11772: Prevalence of Pathogenic Variants in Dilated Cardiomyopathy-Associated Genes in Patients Evaluated for Cardiac Sarcoidosis
Authors: Nosheen Reza, Michael Levin, Mahesh K Vidula, Paco E Bravo, Scott M Damrauer, Marylyn Ritchie, Regeneron Genetics Cntr, Anwar A Chahal, Anjali T Owens
Journal: Circulation (2022)

Introduction: There is phenotypic and mechanistic overlap between arrhythmogenic right ventricular cardiomyopathy and cardiac sarcoidosis (CS). Whether CS and arrhythmogenic left ventricular cardiomyopathy (ALVC) similarly overlap has not been investigated. We aimed to evaluate the difference in proportions of disease-causing variants in ALVC-associated genes in patients with high clinical suspicion for CS. Methods: From a cohort of individuals with whole exome sequencing (WES) with linked electronic health record data in the Penn Medicine BioBank, we identified those who had and had not been referred for FDG-PET and cardiac MRI to evaluate for CS and compared demographics and carrier rates of predicted loss of function (pLOF) variants in genes causal for dilated cardiomyopathy (DCM) and ALVC. Results: Among 43,724 unrelated individuals with WES data, we identified 94 who had been referred for imaging to evaluate for CS. Those who had been referred for imaging were more often of self-reported Black race (50% vs. 25%, p&lt;0.001) and had atrial arrhythmias (62% vs. 30%, p&lt;0.001) and systolic heart failure (61% vs. 17%, p&lt;0.001). Among these 94 individuals, six (6.4%) carried a pLOF variant in at least one of 19 genes known to have strong causal evidence for DCM/ALVC, compared with 1.2% of the participants not referred for imaging. After adjustment for age, sex, and five genetic principal components of ancestry, individuals referred for FDG-PET and MRI were more likely to carry a pLOF variant in a DCM gene of interest compared with the remaining PMBB participants (OR 5.96; 95% CI 2.31, 12.6; p&lt;0.001). Conclusion: Individuals at high clinical suspicion for having CS have 6-fold higher odds of having a pLOF variant in a gene causal for DCM. There is under-recognized overlap between the clinical presentations of genetic ALVC/DCM and CS, and as such, the differential diagnosis for CS and inflammatory cardiomyopathy should be expanded to include these entities.